title: New insights into the binding mode of melanin concentrating hormone receptor-1 antagonists: homology modeling and explicit membrane molecular dynamics simulation study.
abstract: Melanin concentrating hormone (MCH) is a cyclic 19-amino-acid peptide expressed mainly in the hypothalamus. It is involved in the control of feeding behavior, energy homeostasis, and body weight. Administration of MCH-R1 antagonists has been proved to reduce food intake and cause weight loss in animal models. In the present study, a homology model of the human MCH-R1 was constructed using the crystal structure of bovine rhodopsin (PDB: 1u19) as a template. Based on the observation that MCH-R1 can bind ligands of high chemical diversity, the initial model was subjected to an extensive ligand-supported refinement using antagonists of different chemotypes. The refinement process involved stepwise energy minimizations and molecular dynamics simulations. The refined model was inserted into a pre-equilibrated DPPC/TIP3P membrane system and then simulated for 20 ns in complex with structurally diverse antagonists. This protocol was able to explain the SAR of MCH-R1 antagonists with diverse chemical structures. Moreover, it reveals new insights into the critical recognition sites within the receptor. This work represents the first detailed study of molecular dynamics of MCH-R1 inserted into a membrane-aqueous environment.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, Mississippi 38677, United States.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Helal
authors.forename: Amar G
authors.initials: AG
authors.lastname: Chittiboyina
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
mesh_terms: D000818:Animals; D007028:Hypothalamic Hormones / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008543:Melanins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D010907:Pituitary Hormones / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; C019463:melanin-concentrating hormone